According to the Juvenile Diabetes Research Foundation, type 1 diabetes (T1D) afflicts 1-3 million of people in the United States of America and, for reasons yet to be understood, its incidence has been increasing at an alarming annual rate of ~3%. Thus, the number of T1D patients is expected to increase significantly in the next years. T1D occurs as a consequence of pancreatic -cell loss leading to a lethal metabolic imbalance. Current T1D life-saving interventions include daily insulin administrations. These therapies reduce hyperglycemia, glycosylated hemoglobin, cachexia and prevent or delay some of T1D-associated morbidities. However, even with the current and much improved insulin delivery systems, T1D secondary complications include debilitating, long-lasting and economically challenging conditions as for example heart disease, blindness, kidney failure, neuropathy, and hypertension. Probably owing to insulin's lipogenic actions, long-term insulin treatment is suspected to underlie the excessive ectopic lipid deposition (i.e.: in non-adipose tissues) and the extremely high incidence of coronary artery disease (> 90% after age 55) seen in T1D subjects. Furthermore, in part due to insulin's potent, fast-acting, glycemia-lowering effects, intensive insulin therapy significantly increases the risk of hypoglycemia, an event that s disabling and can even be fatal. New and better anti-T1D therapies are therefore urgently needed. A major barrier to the development of new and potentially even insulin-free treatments has been the paradigm that life without insulin is not compatible. This paradigm may need to be revised however after Dr. Roger Unger and colleagues recently reported that leptin monotherapy (without the use of insulin) can reverse the lethal consequences and many of the metabolic defects caused by insulin deficiency in rodent models of T1D. The slow-acting, glycemia-lowering effects of the adipocyte- secreted hormone leptin may therefore represent an attractive alternative and/or adjuvant to current T1D therapies. Here, will directly test the hypothesis that LEPRs in brain and specifically in hypothalamic neurons mediate leptin's anti-T1D action. To directly test our hypothesis, we will assess the metabolic outcomes of CNS-restricted leptin administration in two different mouse models of insulin deficiency. Then, we will make use of other unique genetically-engineered mouse lines to determine the biochemical identity of the neurons mediating these actions. We strongly believe that results from the studies proposed herein will lead to a better understanding of the mechanism(s) by which leptin rescues lethality and improves metabolism in T1D. Once identified, this molecular component(s) can then be exploited to develop new and effective anti-T1D strategies without the risks of hypoglycemia and cardiovascular disease. PUBLIC HEALTH RELEVANCE: According to the Juvenile Diabetes Research Foundation, type 1 diabetes (T1D) afflicts 1-3 million of people in the United States of America and, for reasons yet to be understood, its incidence has been increasing at an alarming annual rate of ~3%. Daily insulin administrations are life-saving for people with T1D but probably owing to insulin's lipogenic actions and potent, fast-acting, glycemia- lowering effects intensive insulin therapy significantly increases the risk of coronary artery disease (> 90% after age 55) and hypoglycemia in T1D subjects. Here, we will perform experiments aimed at identifying the neurocircuitries and molecular mechanisms by which leptin administration ameliorates T1D; we believe that results from the experiments proposed in this application will pave the way to develop better therapeutic approaches against T1D without the risks of hypoglycemia and cardiovascular disease.